The primary objective of this research program is to determine the cause of photoreceptor degeneration in inherited disorders of rd mice and affected Irish setter dogs. In both disorders, a deficiency in the activity of a cyclic nucleotide phosphodiesterase (PDE) results in the accumulation of cyclic GMP. The phosphodiesterase of dark-adapted rod visual cells is activated normally upon exposure to light by a cascade of reactions which is coupled to the photolysis of rhodpsin. The PDE-activation cascade forms apparently the visual transducer process which links photon-capture which changes in membrane polarization. The cascade reaction sequence is serial, providing several sites for discountinuity and, thus, for failure to activate PDE. A functional defect in PDE-activition cascade is proposed in the disorder of Irish setters since all components of the cascade are present in the affected cells whereas a defect in the assemblage of the PDE complex appears to account for blockage of the cascade in rd photoreceptors. This application will investigate the mechanisms that produce the respective lesions and which cause cyclic GMP to accumulate in the affected photoreceptors. We postulate cell death results from the substained action of cyclic GMP-dependent process and, possibly, from the action of a visual cell-specific phosphoprotein. A 33K protein that is complexed with the beta/gamma subunits of transducin is phosphorylated in the dark and dephosphorylated upon illumination of normal photoreceptors. A role for the 33K/T beta gamma complex in the disease process is suggested by the presence of the 33K complex in the inner and outer rod segments and by the accumulation of the 33K complex in affected visual cells of rd mice before cyclic GMP begins to accumulate. It is envisioned that a systematic study of the inherited disorders of rd mice and affected Irish setter dogs will provide a fuller understanding of the respective genetic defects and of the mechanisms by which elevated levels of cyclic GMP initiate photoreceptor degeneration.